March 7, 2013

Specific Brain Region Plays Important Role In Reducing Anxiety

A research team led by the Columbia University Medical Center (CUMC) has found the first evidence that selective activation of the dentate gyrus, a portion of the hippocampus, can reduce anxiety without affecting learning. The findings suggest therapies targeting this brain region could treat certain anxiety disorders, such as panic disorder and post-traumatic stress syndrome (PTSD). These treatments, as described in the study, would have minimal cognitive side effects.

The results of this study, which was conducted in mice, was published online in the journal Neuron.

The dentate gyrus is known by scientists to play a key role in learning, with some evidence suggesting that the structure also contributes to anxiety. "But until now no one has been able to figure out how the hippocampus could be involved in both processes," said Rene Hen, PhD, professor of neuroscience and pharmacology (in psychiatry) at CUMC.

"It turns out that different parts of the dentate gyrus have somewhat different functions, with the dorsal portion largely dedicated to learning and the ventral portion dedicated to anxiety," said Mazen A. Kheirbek, PhD, a postdoctoral fellow in neuroscience at CUMC.

The researchers used a state-of-the-art technique called optogenetics, in which light-sensitive proteins, or opsins, are genetically inserted into neurons in the brains of mice to examine the role of the dentate gyrus in learning and anxiety. With the application of light via a fiber-optic strand, neurons with these genes can then be selectively activated or silenced. This allows researchers to study the function of the cells in real time. Prior to this research, the only way to study the dentate gyrus was to silence parts of it using long-term manipulations with drugs or lesions. These techniques have yielded conflicting results.

The principal cells of the dentate gyrus are the granule cells. The researchers inserted opsins into the granule cells, activating or silencing the ventral or dorsal portions of the dentate gyrus for three minutes at a time. Meanwhile, the mice were subjected to two well-validated anxiety tests — the elevated plus maze and the open field test.

"Our main findings were that elevating cell activity in the dorsal dentate gyrus increased the animals' desire to explore their environment. But this also disrupted their ability to learn. Elevating activity in the ventral dentate gyrus lowered their anxiety, but had no effect on learning," said Dr. Kheirbek. The scientists found that the effects are completely reversible, when the stimulation was turned off the animals returned to their previous levels of anxiety.

"The therapeutic implication is that it may be possible to relieve anxiety in people with anxiety disorders by targeting the ventral dentate gyrus, perhaps with medications or deep-brain stimulation, without affecting learning," said Dr. Hen, who is also director of the Division of Integrative Neuroscience at the New York State Psychiatric Institute (NYSPI) and a member of The Kavli Institute for Brain Science at Columbia. "Given the immediate behavioral impact of such manipulations, these strategies are likely to work faster than current treatments, such as serotonin reuptake inhibitors."

Such intervention would probably work best in individuals with panic disorder or PTSD.

"There is evidence that people with these anxiety disorders tend to have a problem with pattern separation – the ability to distinguish between similar experiences," he said. "In other words, they over-generalize, perceiving minor threats to be the same as major ones, leading to a heightened state of anxiety. Such patients could conceivably benefit from therapies that fine-tune hippocampal activity."

The team is currently exploring strategies aimed at modulating ventral dentate gyrus activity by stimulating neurogenesis in that region of the hippocampus.

"Indeed the dentate gyrus is one of the few areas in the adult brain where neurons are continuously produced, a phenomenon termed adult hippocampal neurogenesis," added Dr. Hen.